The present invention relates to a novel combination of fenofibrate and vitamin E, which is useful as an antiatheromatous drug and exhibits a synergistic effect as regards protection of plasma low density lipoproteins (LDL) from oxidation.
The present invention further relates to a method of using this novel synergistic combination in therapeutic treatments.
Vitamin E, which has the nomenclature .alpha.-tocopherol or 3,4-dihydro-2,5,7,8-tetra-methyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopy ran-6-ol and has the following structural formula: ##STR1## is a vitamin which has antioxidizing properties. Vitamin E is generally used either in the dl form (i.e. the so-called natural form), in the d form (i.e. the more active diastereoisomer), or in an esterified form, especially with acetic acid.
Vitamin E acetate, which is also known as .alpha.-tocopherol acetate or .alpha.-tocopheryl acetate, has the following structural formula: ##STR2## and is generally used in the dl form (i.e. the "standard" product) or the d form.
According to the Merck Index, (1989), 11th edition, pages 1579-1580, entries no. 9931 "Vitamin E" and no. 9932 "Vitamin E Acetate", the international unit (IU) for vitamin E is defined on the basis of dl-.alpha.-tocopherol acetate. This gives rise to the following relationships:
(1) 1 mg of dl-.alpha.-tocopherol acetate=1 IU PA0 (2) 1 mg of d-.alpha.-tocopherol acetate=1.36 IU PA0 (i) the fenofibrate forming part of said combination has previously been co-micronized with a solid surfactant; and PA0 (ii) the above-mentioned ratio Ra is between 0.33 and 2 mg/IU. PA0 (a) a micronized mixture of fenofibrate with a solid surfactant, and PA0 (b) a vitamin E substance selected from the group consisting of tocopherols, their esters with organic acids, and mixtures thereof, PA0 (1) said micronized mixture contains 33 to 200 mg of fenofibrate and the amount of said vitamin E substance represents 100 to 600 IU, and PA0 (2) the ratio (Ra) of the amount of fenofibrate, expressed in mg, to the amount of said vitamin E substance, expressed in IU, is between 0.33 and 2 mg/IU. PA0 (i) a substance belonging to the group consisting of .alpha.-, .beta.-, .gamma.-, .delta., .zeta..sub.1 -, .zeta..sub.2 - and .eta.-tocopherols, and their dl, d and l forms, where appropriate; PA0 (ii) the corresponding esters obtained with organic acids; and PA0 (iii) mixtures thereof. PA0 (.alpha.) the separate daily administration, in the form of gelatin capsules, of (a) 33 to 200 mg of fenofibrate co-micronized with sodium laurylsulfate in association with a physiologically acceptable excipient, and (b) 100 to 600 IU of vitamin E substance (preferably 100 to 600 mg of dl-.alpha.-tocopherol acetate) in association with a physiologically acceptable excipient; and PA0 (.beta.) the daily administration of a single form comprising fenofibrate co-micronized with LSNa, and the vitamin E substance, at the doses in point (.alpha.) above, in which form the vehicles of the two active ingredients are joined or placed side by side (this case is encountered especially when the single form comprises either a tablet of co-micronized fenofibrate and a tablet of vitamin E substance joined by a side or a face, or a gelatin capsule containing said co-micronized fenofibrate and said vitamin E substance together). PA0 (a) a micronized mixture of 33 to 200 mg of fenofibrate with 0.33 to 14 mg of LSNa, and PA0 (b) 100 to 600 mg (i.e. 100 to 600 IU) of dl-.alpha.-tocopherol acetate,
Additionally, as liposoluble antioxidants, vitamin E and vitamin E acetate protect the plasma lipoproteins, and in particular the low density lipoproteins (LDL), from oxidation by free radicals.
Fenobibrate, which has the systematic nomenclature isopropyl 2-4-(4-chlorobenzoyl)phenoxy!-2-methylpropionate or 2-4-(4-chlorobenzoyl)phenoxy!-2-methylpropionic acid 1-methylethyl ester (according to Chemical Abstracts) and has the following structural formula: ##STR3## is a hypolipidemic which also lowers cholesterolemia and triglyceridemia.
U.S. Pat. No. 4,895,726, counterpart of EP-A-0 330 532 discloses a solution for improving the bioavailability of fenofibrate, herein a unit dose of 200 mg of fenofibrate, which was previously co-micronized with a solid surfactant, is therapeutically equivalent to a dose of 300 mg of fenofibrate, which was micronized in the absence of a solid surfactant.
Finally, the capacity of fenofibrate to protect lipoproteins from oxidation has been studied in the article entitled "Antioxidant Therapy and Uptake of Human oxidized LDL by Macrophages" by J. C. FRUCHART et al., Annals of the New York Academy of Sciences, 1989, vol. 570, pp. 447-448. According to said article, the LDL of hypercholesterolemic patients who had received 300 mg/d of fenofibrate, 1000 mg/d of vitamin E (i.e. dl-.alpha.-tocopherol) or the combined treatment of 300 mg/d of fenofibrate and 1000 mg/d of vitamin E for two months were isolated and then oxidized by incubation (24 h) with copper, before being transferred and incubated (5 h) in a culture of mouse peritoneal macrophages in order to study the uptake of LDL.
The results given in said article indicate that (i) the uptake of LDL in the group of patients who had received fenofibrate is identical to that in the control group, meaning that said fenofibrate has no effect on the oxidation of the LDL, and (ii) the rate of uptake of LDL decreases by 19.9% for the group which had received vitamin E and by 22.4% for the group which had received the fenofibrate/vitamin E combination.
It was found according to the present invention, that the incubation period of 24 h for oxidizing LDL with copper (according to J. C. FRUCHART et al.) is too long and that the results obtained are consequently rather imprecise and unreliable.
Therefore, there is a need for a novel drug for the treatment and/or prevention of atheromatous diseases.
Accordingly, the present invention relates to a combination of fenofibrate and vitamin E which is genuinely effective in protecting plasma lipoproteins in particular, especially LDL and, if appropriate, the very low density lipoproteins (VLDL), from oxidation.
The solution which is recommended for this purpose utilizes a combination of fenofibrate and vitamin E wherein:
the fenofibrate has previously been co-micronized with a solid surfactant, and PA1 the ratio Ra of the amount of fenofibrate (expressed in mg) to the amount of vitamin E (expressed in IU) is greater than 0.3 mg/IU, in contrast to the teaching of the article by J. C. FRUCHART et al. cited above.
The present invention is based on two discoveries. The first is that, while fenofibrate which has not been co-micronized with a solid surfactant has practically no protective effect on LDL plasma lipoproteins with respect to oxidation according to J. C. FRUCHART et al., fenofibrate which has been co-micronized with a solid surfactant does protect said lipoproteins from oxidation.
The second discovery is that the fenofibrate/vitamin E substance combination exhibits a synergistic effect as regards protection of lipoproteins, such as LDL, from oxidation when the following two conditions are satisfied:
According to a first feature of the present invention, a novel combination of fenofibrate and a vitamin E substance is recommended which comprises:
with the following two conditions:
According to a second feature of the present invention, a novel method of using said co-micronized fenofibrate/vitamin E substance combination is recommended for the preparation of a drug intended for use in therapeutics for the treatment and prevention of atheromatous diseases.